The goal of Project 1 is to use a genetic approach to identify the genes and pathways responsible for the development of Immunoglobulin A nephropathy (IgAN). IgAN is the most common form of primary glomerulonephritis and a significant cause of renal failure worldwide. The primary etiology of this disorder is unknown and there is no effective treatment currently available. By a genome-wider analysis of linkage, we have shown that in 60% of families with IgAN the disease is linked to an interval on chromosome 6q22-23, now called IGAN1. This genetic interval is supported with a peak lod score of 5.6 and confines the location of the disease gene to a 6.5 cM region. We now propose to replicate our findings in a new set of pedigrees, and narrow the IGAN1 interval to permit identification of the underlying gene. This will be accomplished by meiotic mapping in 20 newly recruited kindreds with IgAN and by disequilibrium mapping using a dense set of single nucleotide polymorphisms in 150 patients with sporadic IgAN who will be recruited from the southeastern United States. We will then proceed to positionally clone the underlying gene. Secondly, we plan to research for additional IgAN loci and study the significance of IGAN1 and these other loci in the pathogenesis of a related disorder, Henoch Schonlein purpura. Finally, using the information gathered by Core A and Projects 2 and 3 of this Program Project, we will perform genotype-phenotype correlation studies to determine the role of allelic and locus heterogeneity on the development of IgAN of IgAN and its complications.